Approach To Patients With Unintentional Weight Loss

A p proac h t o Pat i en t s wi th
U n i n t e n t i o n a l We i g h t L o s s
a,1 b,1
Liyanage Ashanthi Menaka Perera, MD , Aparna Chopra, MBBS ,
Amy L. Shaw, MDc,*
KEYWORDS
Weight loss Unintentional weight loss Involuntary weight loss
Unintended weight loss Malignancy Older adults
KEY POINTS
Unintentional weight loss is a common problem, especially in older adults, and is associ-
ated with increased mortality.
The most common causes are malignancy, nonmalignant gastrointestinal diseases, and
psychiatric disorders in community-dwelling adults; psychiatric disorders are the most
common cause identified in institutionalized older adults.
Treatment of unintentional weight loss is aimed at managing the underlying causes.
INTRODUCTION
Unintentional weight loss can be an enigma for internists. It is a nonspecific condition

that may come to light either through the observations of a discerning family member
or physician or as a chief complaint from the patient themselves. The differential diag-
nosis is broad, and the clinician is then faced with the task of ascertaining how and
where to begin the search for a cause. In this review, the authors aim to summarize
the potential causes of unintentional weight loss and review treatment options. They
also offer insight into the management of unintentional weight loss in older adults.
In the literature, unintentional weight loss is used synonymously with “involuntary”
or “unintended” weight loss. It is used to describe situations whereby weight loss oc-
curs without effort on the part of the patient and whereby it is not an expected conse-
quence of the treatment of a known medical condition or illness, such as diuretic
a
Department of Medicine, Division of Hospital Internal Medicine, Mayo Clinic, 1000 First Drive
NW, Austin, Minnesota, 55912, USA; b Institute for Critical Care Medicine, The Mount Sinai
Hospital, 1468 Madison Avenue, Guggenheim Pavilion 6 East, Room 378, New York, New York,
USA; c Department of Medicine, Division of Geriatrics and Palliative Medicine, Weill Cornell
Medicine, 525 East 68th Street, Box 39, New York, NY 10065, USA
1
Co-first author.
* Corresponding author.
E-mail address: als9138@med.cornell.edu
Twitter: @amyshawmd (A.L.S.)
Med Clin N Am 105 (2021) 175–186

https://doi.org/10.1016/j.mcna.2020.08.019 medical.theclinics.com
0025-7125/21/ª 2020 Elsevier Inc. All rights reserved.
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reservados.
176 Perera et al
therapy for heart failure exacerbation. Furthermore, unintentional weight loss is not
synonymous with other wasting disorders, such as sarcopenia or cachexia. Sarcope-
nia is a multifaceted geriatric syndrome characterized by progressive loss of skeletal
muscle mass and strength; it is attributed to primary (age-related) or secondary (multi-
morbidity-related) causes, and it is often associated with debility, poor quality of life,
and death.1 Cachexia, on the other hand, describes muscle loss in the setting of un-
derlying illness, often associated with anorexia, inflammation, and insulin resis-
tance.2,3 Although these conditions are not synonymous with unintentional weight
loss, patients may develop both sarcopenia and cachexia as a result of their weight
loss.
NATURE OF THE PROBLEM
Several large studies have shown an association between unintentional weight loss
and mortality in specific populations, including American women aged 55 to 69,4
British men aged 56 to 75,5 and overweight and obese American people aged 35
and over.6
The connection between unintentional weight loss and mortality is especially impor-
tant given that unintentional weight loss is not uncommon. One large survey study
among people 45 years of age and older found that 5% of participants reported unin-
tentional weight loss of at least 5% in the preceding 12 months; unintentional weight
loss was associated with older age, smoking, and poorer health status.7 In the longer
term, approximately 15% to 20% of people 65 years of age and older are estimated to
develop unintentional weight loss over 5 to 10 years.8
DEFINITIONS
Beginning in the third decade of life, physiologic changes to body mass composition
as a result of the normal process of aging leads to lean body mass decline at a rate of
0.3 kg/y with a simultaneous increase in body fat. The net result of these changes is an
increase in total body weight that peaks in the fifth to sixth decade of life, with weight
remaining stable until age 65 to 70.9 By the seventh decade, patients begin to lose
weight at a rate of 0.1 to 0.2 kg/y; unintentional weight loss exceeding these param-
eters is considered abnormal.10 Although there is not yet a consensus on what consti-
tutes clinically significant weight loss, many studies in the literature have used a cutoff
of 5% loss of usual body weight over a span of 6 to 12 months as the definition of clin-
ically significant weight loss warranting further medical evaluation.11
PATHOPHYSIOLOGY
Cancer cachexia may provide insight into the biological mechanisms behind uninten-
tional weight loss. The proinflammatory cytokines, tumor necrosis factor alpha,
interleukin-1, and interleukin-6, are implicated in driving cancer cachexia by promot-
ing anorexia as well as muscle and fat catabolism.12
In order to maintain body weight homeostasis, energy intake must be equivalent to
energy expenditure. In cancer cachexia, however, the decreased caloric intake does
not result in decreased energy expenditure12; rather, it is a hypermetabolic state with
an upregulation in the biochemical processes of gluconeogenesis, protein breakdown,
lipolysis,13 and lactate recycling.12 For example, resting energy expenditure has been
shown to be elevated in patients with lung cancer, and higher resting energy expen-
diture is correlated with higher levels of the inflammatory marker C-reactive protein.14
Leptin, a hormone produced by adipocytes, acts upon the receptors of the
reservados.
Patients with Unintentional Weight Loss 177
hypothalamus to produce a negative feedback mechanism that results in satiety and

decreased food intake. Although patients with caloric deprivation and those with can-
cer cachexia have low leptin levels, patients with cancer cachexia do not have the
normal resulting increase in appetite and decrease in energy expenditure; inflammation
is thought to interfere with the normal feedback system.15 The metabolic, hormonal,
and cytokine dysregulation seen in cancer cachexia demonstrates the complexity of
the mechanisms that potentially lie behind undifferentiated unintentional weight loss.
CAUSES OF UNINTENTIONAL WEIGHT LOSS
Unintentional weight loss is a marker for serious underlying pathologic condition.

Several studies that investigated causes of unintentional weight loss found that malig-
nancy is the most common cause, found in 15% to 37% of patients.16–18 Nonmalig-
nant gastrointestinal causes (particularly malabsorption disorders) constitute 10% to
20% of cases,17–20 whereas psychiatric disorders (particularly depression) make up
another 10% to 23% of cases of unintentional weight loss.16–18 Surprisingly, another
25% of cases do not find a cause for unintentional weight loss despite a thorough
workup.16,17 It is important to note that many studies describing the causes of uninten-
tional weight loss have been conducted at referral centers after some initial workup
was unrevealing, so the true distribution of causes in primary care may be different.
In other words, studies from referral centers may reflect the causes that are found after
the most common causes have been elicited in primary care. It is also important to
note that advances in imaging and other medical technology may reduce the propor-
tion of patients with idiopathic weight loss in current practice compared with the pro-
portion of these patients in older studies. Conditions to consider in the differential
diagnosis of unintentional weight loss are described in detail in later discussion.
Malignancy
Malignancies are associated with anorexia and weight loss at the time of diagnosis,
particularly upper gastrointestinal cancer (80%) and lung cancer (60%).21 Workup
for weight loss associated with malignancy may require additional testing. In a pro-
spective cohort study conducted by Metalidis and colleagues,22 among 101 patients,
all 22 patients who had an underlying malignancy had abnormal laboratory test results,
including C-reactive protein, hemoglobin, lactate dehydrogenase, and albumin. How-
ever, imaging studies, such as ultrasound and chest radiographs, had lower sensitiv-
ities (45% and 18%, respectively).
Cardiovascular Disease
Congestive heart failure can lead to both sarcopenia and cachexia, although edema
may mask the diagnosis of weight loss.23 Cachexia predicts mortality in heart failure
independent of factors, such as age, New York Heart Association symptom class,
and left ventricular ejection fraction.23 Various factors have been implicated in the
pathophysiology of cardiac cachexia, which involves alterations in energy expenditure
and catabolic-anabolic balance. These factors include both increased production of
the proinflammatory cytokines, interleukin-1, interleukin-6, and tumor necrosis factor
alpha, and increased sympathetic nervous system activity with resulting stimulation of
the renin-angiotensin-aldosterone system.24
Respiratory Disease
Chronic weight loss that is associated with severe lung disease is called pulmonary
cachexia syndrome. Approximately 25% of patients with chronic obstructive
reservados.
178 Perera et al
pulmonary disease are estimated to develop cachexia; the pathophysiology of weight

loss is likely related to disuse atrophy, tissue hypoxia, systemic inflammation, and
neurohormonal dysregulation, including insufficiency of anabolic hormones and sym-
pathetic upregulation.25 The pattern of weight loss is frequently episodic, with a
decline associated with each acute exacerbation. Glucocorticoid treatment may com-
pound the loss of lean body mass.26 Other pulmonary conditions associated with un-
intentional weight loss may overlap with inflammatory (eg, interstitial lung disease and
ANCA-associated vasculitis), infectious (eg, tuberculous and nontuberculous myco-
bacterial infections), and malignant (eg, lung cancer) conditions, illustrating that
causes of weight loss commonly involve more than 1 body system.
Gastrointestinal Disease
A thorough history and physical examination may reveal symptoms suggestive of
gastrointestinal disease. These clinical features include abdominal pain, early satiety,
dysphagia, odynophagia, steatorrhea, hematochezia, melena, abdominal tenderness,
and abdominal masses. Although gastrointestinal malignancy, inflammatory bowel
disease, and malabsorption (eg, pancreatic insufficiency and celiac sprue) are
commonly thought of as gastrointestinal causes of weight loss, clinicians should
also consider conditions such as peptic ulcer disease, mesenteric ischemia, and
protein-losing enteropathies.26 The mouth and pharynx are important parts of the
gastrointestinal tract, and mechanical difficulties, such as dysphagia, odynophagia,
and poor dentition, from any cause may contribute to weight loss by affecting the
desire or ability to chew and swallow food.27
Endocrinopathies
Hyperthyroidism is associated with accelerated weight loss and increased appetite.28
Patients with uncontrolled diabetes mellitus may experience weight loss along with
other symptoms of hyperglycemia, such as polyuria and polydipsia.29 Primary adrenal
insufficiency may present with the nonspecific symptoms of weight loss, nausea, and
fatigue.30
Rheumatologic Disease
Unintentional weight loss may be a presenting symptom in certain rheumatological
conditions, particularly rheumatoid arthritis, where the term “rheumatoid cachexia”
describes a loss of skeletal muscle and gain of fat mass.31 Giant cell arteritis may
also be associated with weight loss,32,33 as may autoimmune and inflammatory con-
ditions mentioned elsewhere, such as inflammatory bowel disease and ANCA-
associated vasculitis.
Infectious Disease
AIDS can lead to episodic weight loss related to secondary opportunistic infections,
low CD4 count states, and malabsorptive gastrointestinal diseases. The mechanism
for weight loss is multifactorial but primarily related to increased energy expenditure
during opportunistic infections and excessive cytokine activation states coupled
with reduced oral intake that leads to protein-calorie malnutrition resembling wasting
and starvation.34–36 Other infectious diseases, such as active and reactivation tuber-
culosis, chronic hepatitis C, and helminthic infections, can commonly present with
weight loss. Clinicians should consider local disease patterns and patient travel history
when investigating possible infectious disease.
reservados.
Neurodegenerative and Psychiatric Disease

Weight loss is commonly seen in neurodegenerative diseases, such as Alzheimer-type
dementia, Parkinson disease, and Huntington disease; in Alzheimer disease and Par-
kinson disease, weight loss may precede diagnosis.37,38 Related cognitive impairment
may cause difficulty remembering to eat or preparing food. Psychiatric disorders,
particularly depression, are a common cause of unintentional weight loss. A prospec-
tive study of 2677 patients with unintentional weight loss found 16% of cases were the
result of psychiatric conditions.16 The proportion of people with unintentional weight
loss attributed to psychiatric causes can exceed 50% in nursing home resi-
dents.16,39,40 Patients of all ages, genders, and races may suffer from eating disorders;
patients with eating disorders may present to primary care with a variety of concerns
before an eating disorder is diagnosed.41
Medications and Substances

Weight loss is a common adverse effect of many medications. Anticonvulsants (top-
iramate), antidepressants (bupropion), and stimulants eg. methylphenidate, dextro-
amphetamine can cause weight loss as a result of appetite suppression. Other
classes of medications can lead to unintentional weight loss as a result of decreased
oral intake from medication-induced nausea and vomiting (selective serotonin reup-
take inhibitors, tricyclic antidepressants, dopamine agonists, metformin, digoxin), al-
terations in taste and smell (angiotensin converting enzyme inhibitors, calcium channel
blockers, spironolactone, allopurinol), and dry mouth (anticholinergic medications).
Dysphagia as a result of pill esophagitis from medications, such as bisphosphonates,
doxycycline, potassium supplements, and nonsteroidal anti-inflammatory drugs, can
also limit oral intake. Gastrointestinal symptoms, such as diarrhea, potentiate the ef-
fect of weight loss and are a commonly experienced adverse effect of medications,
such as metformin, glucagon-like peptide-1 agonists, and laxatives.8,11,42
In addition to prescribed medications, other substances can also lead to weight
loss. Although the mechanism is still unclear, cocaine is thought to cause weight
loss in part through appetite suppression as well as by dysregulation of fat metabolism
leading to reduction in fat body mass.43 Amphetamines and their stimulant derivatives
cause weight loss through appetite suppression and increased energy expenditure.
Excess alcohol consumption and dependence can lead to a nutrition-deficient diet
of “empty calories” leading to malnutrition and subsequently weight loss.
Clinicians must gather a complete history of all medications and substances taken by
patients, being aware that patients may obtain prescription drugs from other clinicians
or from other people (ie, by using a prescription written for someone else) and may use
over-the-counter medications or supplements that can contribute to weight loss.
Psychosocial Factors
Social determinants of health, such as socioeconomic status, physical environment,
and social support networks, can affect access to food, leading to unintentional
weight loss. Patients with functional or cognitive impairment may have difficulty per-
forming tasks, such as grocery shopping and preparing food. Clinicians should be
aware that older adults, especially those with cognitive impairment who depend on
caregivers, are at increased risk for elder abuse and neglect.
CAUSES OF WEIGHT LOSS IN OLDER ADULTS
Unintentional weight loss is common in older adults and occurs in about 15% to 20%
of geriatric patients.44 It is even more prevalent in high-risk populations, such as
reservados.
180 Perera et al
nursing home residents, with estimates of up to 60%.45 Unintentional weight loss in

older adults is associated with an increased risk of mortality even when controlling
for potential confounders like smoking and alcohol use,46 sedentariness,44 and
comorbidities.44,46,47 It is also associated with a decline in activities of daily living,44,48
decreased quality of life,49 increased risk of hip fractures,50 and increased hospital
length of stay and complications.51 Unintentional weight loss in older adults is even
associated with subsequent admission to long-term care institutions.52 Risk factors
for unintentional weight loss in this patient population include presence of comorbid-
ities, low body weight, smoking, low education level, loss of a spouse,7 and cognitive
impairment.38
The causes of unintentional weight loss in older adults are similar to the causes of
unintentional weight loss in the general population, with malignancy being the most
common cause (16% to 36%), followed by nonmalignant gastrointestinal diseases
(10% to 20%) and psychiatric disorders, such as depression or dementia (10% to
23%), in community-dwelling older adults.16,17,19,42,53 In long-term care facilities, psy-
chiatric disorders are the most common cause of unintentional weight loss.40
Unlike their younger counterparts, older adults more often have multiple causes of
unintentional weight loss related to the physiology of aging and the interplay of chronic
medical conditions. Older adults may have decreased appetite as a result of
decreased energy requirements, due in part to decreases in lean muscle mass and in-
creases in total body fat. However, this becomes pathologic when the degree of loss
of appetite becomes disproportionately higher than the reduction in energy expendi-
ture, and subsequently, weight loss exceeds the expected small loss in weight with
age.54 Physiologic changes related to aging, such as decreased taste and olfactory
sensation and slower gastric emptying coupled with early satiation, contribute to
reduced pleasure or interest in eating and predispose older adults to weight loss.55
The presence of oropharyngeal and esophageal disorders related to dental decay,
dry mouth, and dysphagia can potentiate this effect and further precipitate weight
loss. Polypharmacy can alter taste-smell sensorium and can increase the likelihood
of anorexia-related adverse effects of medications. Furthermore, socioeconomic con-
straints, such as limitations in obtaining and preparing food, may be significant, espe-
cially in frail, socially isolated older adults.
APPROACH
The workup of unintentional weight loss relies on a thorough history and physical ex-
amination to diagnose disease and guide testing (Fig. 1). A clinical history should
include the amount and pace of weight loss; dietary assessment; psychosocial fac-
tors; and associated symptoms, such as joint pain, dyspnea, diarrhea, gastrointestinal
bleeding, dental problems, and depressed mood. Clinicians should review all medica-
tions, supplements, and chronic medical conditions. A physical examination can
reveal signs of weight loss, such as temporal wasting and loose clothing. It can also
reveal signs of serious illness, such as lymphadenopathy, joint swelling, cardiopulmo-
nary abnormalities, organomegaly, and masses (eg, on prostate, breast, and abdom-
inal examination). Oral examination may show poor dentition or painful lesions, and
cognitive screening may alert clinicians to impairment.11,26,56
The authors suggest that the initial laboratory, radiologic, and other testing be
guided by the results of the history and physical examination. For example, endos-
copy would be considered early in the workup of a patient with weight loss, melena,
abdominal pain, and early satiety but would not be part of the initial evaluation for
weight loss in general. Laboratory tests to consider include a complete blood count
reservados.
Fig. 1. Suggested initial workup of unintentional weight loss. (Data from Refs.11,26,56)
to look for infection, anemia, and lymphoproliferative disorders; a comprehensive

metabolic panel to look for diabetes, liver disease, renal insufficiency, and electrolyte
abnormalities; a thyroid function profile to rule out hyperthyroidism; lactate dehydro-
genase, which may be elevated in malignancy; inflammatory markers, such as eryth-
rocyte sedimentation rate and C-reactive protein, which may be elevated in
inflammatory, malignant, or infectious conditions; and tests for HIV and chronic viral
hepatitis. Testing for chronic viral hepatitis should be considered based on risk
reservados.
182 Perera et al
factors. One-time fecal occult blood testing is often used to screen for colon cancer
but is neither sensitive nor specific; a negative result does not rule out bleeding or ma-
lignancy, so diagnostic studies, such as endoscopy and colonoscopy, may become
necessary if there is suspicion for gastrointestinal malignancy or inflammatory condi-
tions. Imaging studies, such as computed tomography, may be pursued if indicated
based on the history, physical examination, and initial tests.11,56 Age-appropriate can-
cer screening should be pursued if it is not up-to-date.
If this workup reveals abnormal results suggestive of a particular cause of the unin-
tentional weight loss, then a targeted evaluation and treatment of the underlying cause
are indicated. If these studies are uniformly normal, then the patient should be moni-
tored over the next 3 to 6 months to look for additional weight loss or signs and symp-
toms to guide further workup.
THERAPEUTIC OPTIONS
Treatment of patients with unintentional weight loss involves treating the underlying
cause. A thorough history and physical examination are vital in order to identify the
cause of weight loss and can be supplemented by laboratory tests as well as age-
appropriate cancer screening. An interprofessional approach, including dietitians,
speech therapists (for evaluation of oropharyngeal dysphagia), and social services,
is imperative in treating unintentional weight loss.40
Several medications, most commonly mirtazapine, dronabinol, and megestrol, have
been used to promote weight gain, although side effects may limit their use. These
medications have also not been shown to improve mortality in older adults with unin-
tentional weight loss.8,11 Mirtazapine, a selective serotonin reuptake inhibitor, may be
used to treat patients with depression who have reduced appetite; treatment improves
appetite and promotes weight gain, but adverse effects include dry mouth, dizziness,
orthostatic hypotension, and excessive sedation.11,57 Dronabinol, a cannabinoid, has
been used for the treatment of anorexia in patients with AIDS but can have central ner-
vous system toxicity, including confusion and somnolence.11,40 Although megestrol
has been found to improve appetite and promote weight gain in patients with cancer
and patients with AIDS-related anorexia-cachexia syndrome, it is also associated with
adverse effects, such as edema, thromboembolic events, and death.58
In older adults, altering the consistency of food can help accommodate patients
with poor dentition or dysphagia. Reducing dietary restrictions, such as low-fat or
low-salt diets, may be appropriate to make food more palatable. Nutritional supple-
ments can provide extra calories but should not replace meals; they may be more
effective when given between meals.59 Weight loss refractory to oral nutritional sup-
plementation may elicit questions from patients, families, and clinicians about feeding
tube placement. This discussion must incorporate patient and caregiver preferences
as well as acknowledgments of risks and benefits of tube feeding.40 Tube feeding is
associated with higher mortality in nursing home residents with dysphagia compared
with residents without tube feeding, even when adjusted for factors such as weight
loss and pressure injury.60 Feeding tubes may need to be replaced or repositioned.61
Furthermore, percutaneous endoscopic gastrostomy tube placement improves
neither mortality nor albumin levels in patients with dementia compared with patients
having PEG placement for other neurologic diseases or head and neck cancers.62 It
should be noted that decision-making about tube feeding in nursing home patients
and patients with dementia may differ from decision-making about tube feeding in pa-
tients with other conditions, especially those whose underlying condition is expected
to improve.60
reservados.
SUMMARY
Clinically significant weight loss is defined as a loss of at least 5% of body weight over
6 to 12 months. There is an increase in morbidity and mortality associated with unin-
tentional weight loss. The differential diagnosis of involuntary weight loss is broad and
requires consideration of physiologic, pathologic, and psychosocial factors. Treat-
ment largely depends on targeting the underlying cause; therefore, clinicians must
perform a thorough history and physical examination and consider laboratory testing
and cancer screening when evaluating a patient with unintentional weight loss.
CLINICS CARE POINTS

Many studies define clinically significant weight loss as at least 5% of usual body
weight over 6 to 12 months (source 11).
Weight loss is associated with many chronic diseases.
A careful medication history is essential in the workup of weight loss; medica-
tions may lead to weight loss through several mechanisms.
Nutritional supplements should be used to supplement rather than replace reg-
ular meals (source 59).
DISCLOSURE
Dr. Shaw supported in part by a Joachim Silbermann Family Clinical Scholar Award in
Geriatrics from the Rosanne H. Silbermann Foundation.
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Approach To Patients With Unintentional Weight Loss

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Approach To Patients With Unintentional Weight Loss

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A p proac h t o Pat i en t s wi th

Unintentional weight loss can be an enigma for internists. It is a nonspecific condition

Med Clin N Am 105 (2021) 175–186

NATURE OF THE PROBLEM

hypothalamus to produce a negative feedback mechanism that results in satiety and

CAUSES OF UNINTENTIONAL WEIGHT LOSS

Unintentional weight loss is a marker for serious underlying pathologic condition.

pulmonary disease are estimated to develop cachexia; the pathophysiology of weight

Neurodegenerative and Psychiatric Disease

Medications and Substances

CAUSES OF WEIGHT LOSS IN OLDER ADULTS

nursing home residents, with estimates of up to 60%.45 Unintentional weight loss in

to look for infection, anemia, and lymphoproliferative disorders; a comprehensive

CLINICS CARE POINTS

1. Santilli V, Bernetti A, Mangone M, et al. Clinical definition of sarcopenia. Clin

Descargado para Mister bdbd (misterbd2000@gmail.com) en University of Rosario de

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